Dry eye syndrome is a common clinical condition characterized by deficient tear production or excessive tear evaporation, which may be caused by a variety of causative factors. For example, lacrimal gland inflammation (dacryoadenitis) and corneal denervation may curb tear production, whereas meibomian gland dysfunction and eyelid disorders such as incomplete lid closure are frequently to blame for rapid tear evaporation. Further, T-cell-mediated inflammatory responses were reported responsible for the pathogenesis of dry eye syndrome (Eye Contact Lens, 29(1 Suppl):S96-100, 2003; and Opthalmologe, 103:9-17, 2006).
A tear film continuously secretes a given amount of tears which will not only provide sterilizing effects, but also participate in smooth covering and lubrication of ocular surfaces to play an important role in maintenance of one's eyesight. Three main layers make up the tear film. Specifically, the innermost layer is a layer of mucin produced by conjunctival goblet cells, the middle layer is an aqueous layer secreted by the lacrimal gland, and the most superficial layer is a very thin layer of lipids (fats or oils) secreted by the meibomian gland.
Usually, patients with dry eye syndrome may experience burning and stinging, grittiness or foreign-body sensation, itching, redness, and the other symptoms of ocular discomfort. In severe cases, vision may be substantially impaired. At first, dry eye syndrome was recognized as a characteristic sign of aging which is common among women of post-menopausal age. With recent increases in TV watching, use of computers, and wearing of contact lens, this condition becomes frequent in both men and women. Further, the onset age of dry eye syndrome is gradually decreasing (Gynecol Endocrinol, 20:289-98, 2005; and Surv Opthalmol, 50:253-62, 2005).
As approaches to remedy dry eye syndrome, mention may be made of instillation of artificial tears for artificial tear supplementation, instillation of steroidal anti-inflammatory eye drops to inhibit inflammatory responses, therapeutic contact lens (TCL) wear, surgical occlusion of the punctum to suppress tear escape from one's eye to result in prolonged ocular retention of artificial tear solutions or substitutes, and the like (J Korean Opthalmol Soc, 46:1774-1779, 2005). These therapeutic approaches have been widely used up to recently, but pose a variety of potential disadvantages and problems. For example, artificial tear preparations merely provide temporary and short-term effects, thus suffering from disadvantages such as the need for several daily applications of the tear preparations and no protective effects against corneal damage, whereas steroid preparations may cause the risk of irreversible side effects such as glaucoma, upon chronic administration of the steroid drug. In addition, therapeutic contact lens may provide inconvenience to users who are unfamiliar with wearing of contact lens, and may also be a potential source of bacterial infections. Further, the punctual occlusion surgery still suffers from disadvantages such as mental rejection feelings due to the surgical operation, and difficulty to restore the former state upon the occurrence of adverse side effects. However, the most glaring weakness of the aforementioned conventional remedies is in that they are merely symptomatic therapies, which are not focused to treat or address the root causes of dry eye conditions.
In 2006, the US company Allergan, Inc. developed and released Restasis (cyclosporine ophthalmic emulsion) which is a therapeutic agent for the treatment of dry eye syndrome using the immunomodulator cyclosporine. Restasis has recently been reported to inhibit the production and activation of immunocytes associated with the occurrence of keratoconjunctivitis sicca and to increase the tear secretion level (Opthalmology, 107:967-74, 2000; and Opthalmology, 107:631-9, 2000). Restasis exerts drug efficacy thereof via anti-inflammatory action, so long-term repeated drug administration of several months is unfortunately required to achieve therapeutic effects that are satisfactory to patients. Further, administration of Restasis is disadvantageously accompanied by relatively high frequency of occurrence (17%) of a typical side effect, e.g. burning sensation (Opthalmology, 107:631-9, 2000; and Thomson Pharma, www.thomson-pharma.com).
To this end, there is an urgent need for development of a therapeutic agent which is not a symptomatic therapeutic merely palliating symptoms of the concerned condition and is capable of treating the root causes of dry eye syndrome while securing safety of drug medications due to low manifestation of adverse side effects.
Dry eye syndrome is a multifactorial disease which is caused by diverse pathogenic causes as discussed hereinbefore, and a variety of approaches have been attempted to treat such a condition. Inter alia, a great deal of research has been actively focused on lacrimal secretion stimulants, i.e. tear stimulants. For example, attempts have been made to develop a drug that stimulates lacrimation (tear secretion) of lacrimal acinar cells through the medium of cholinergic neurotransmission or increases lacrimal flow of the conjunctiva via stimulation of purinergic receptors (Arthritis Rheum, 46:748-54, 2002; and Curr Eye Res, 21:782-7, 2000). In particular, an ocular mucin layer lowers the surface tension of water to allow uniform distribution of water throughout the ocular surface and plays an important role to provide corneal protection against a hostile external environment, such as ocular damage or infection by foreign materials or pathogenic agents. Therefore, many extensive animal-based preclinical and human-based clinical studies have been actively undertaken to find drugs that stimulate secretion of mucins from conjunctival goblet cells (Exp Eye Res, 67:341-6, 1998; Cornea, 21:818-24, 2002; Cornea, 23:613-9, 2004; and Thomson Pharma, www.thomson-pharma.com).
Mucus is composed mainly of mucin and inorganic salts. Mucin consists of carbohydrates and proteins and is responsible for protection of mucosal epithelial cells and lubricating action. To date, 21 different human mucin genes have been identified. Ocular mucin genes include 9 classes of genes, designated MUC1, MUC2, MUC4, MUC5AC, MUC7, MUC13, MUC15, MUC16 and MUC17, which may be further subdivided into transmembrane mucin and secretory mucin (Prog Retin Eye Res, 23:449-74, 2004). Substances having stimulatory activity on secretion of transmembrane and secretory mucins in tear films can be therapeutically effective for the treatment of dry eye syndrome by prevention of corneal damage which may arise from excessive eye dryness.
As a result of a variety of extensive and intensive studies and experiments to solve the problems as described above and to cope with the need for development of an effective therapeutic agent for the treatment of dry eye syndrome, the inventors of the present invention succeeded in synthesis of novel 3′,4′,5-trimethoxy flavone derivatives and pharmaceutically acceptable salts thereof and discovered that these compounds exhibit excellent effects on stimulation of conjunctival mucus secretion and inhibition of ocular surface damage. Further, the present inventors discovered that 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone monohydrates, previously studied in Korean Patent Nos. 447918, 327621 and 644928 assigned to the present applicant, have anti-inflammatory activity, gastric mucus secretion-stimulating activity and conjunctival mucus secretion-promoting activity, thereby providing pronounced inhibitory effects on the occurrence of ocular surface damage. The present invention has been completed based on these findings.